User:Mevans86/Vicinal difunctionalization of unsaturated carbonyls

Vicinal difunctionalization refers to a chemical reaction involving transformation at two adjacent centers (most commonly carbons). This can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile to the β-position followed by trapping of the resulting enolate with an electrophile at the α-position. When the nucleophile is an enolate and the electrophile a proton, the reaction is called Michael addition.

Introduction
Vicinal difunctionalization reactions, most generally, lead to new bonds at two adjacent centers. Often this takes place in a stereocontrolled fashion, particularly if both bonds are formed simultaneously, as in the Diels-Alder reaction. Activated double bonds represent a useful handle for vicinal difunctionalization because they can act as both nucleophiles and electrophiles—one carbon is necessarily electron poor, and the other electron rich. In the presence of a nucleophile and an electrophile, then, the two carbons of a double bond can act as a "relay," mediating electron flow from the nucleophile to the electrophile with the formation of two, rather than the usual one, chemical bonds. Most often, the nucleophile employed in this context is an organometallic compound and the electrophile is an alkyl halide.

Prevailing Mechanism
The mechanism proceeds in two stages: β-addition to the unsaturated carbonyl compound, followed by nucleophilic substitution at the α-carbon of the resulting enolate.

When the nucleophile is an organometallic reagent, exact mechanisms of the first step can vary slightly. Whether reactions take place by ionic or radical mechanisms is unclear in some cases. Research has shown that the second step may even proceed via single-electron transfers when the reduction potential of the electrophile is low. A general scheme involving ionic intermediates is shown below. For lithium organocuprates, a single-electron transfer mechanism has been suggested and supported by experimental data. For other nucleophiles, exact mechanisms are less clear. Grignard reagents appear to react via a single-electron-transfer mechanism, and enolates may react by a SET-type mechanism or via an SN2' process.

In any case, the second step is well described in all cases as the reaction of an enolate with an electrophile. The two steps may be carried out as distinct experimental operations if the initially formed enolate is protected after β-addition. If the two steps are not distinct, however, the counterion of the enolate is determined by the counterion of the nucleophilic starting material, and can influence the reactivity of the enolate profoundly.

Stereochemistry
Steric approach control is common in conjugate addition reactions. Thus in cyclic substrates, trans stereochemistry at the β-carbon is common. The stereochemistry at the α-position is less predictable, especially in cases when the α-position can epimerize. On the basis of steric approach control, the new α-substituent is predicted to be trans to the new β-substituent, and this is observed in a number of cases.

Scope and Limitations
Organocopper reagents are the most common nucleophiles for the β-addition step. These can be generated catalytically in the presence of Grignard reagents using either copper(I) or copper(II) catalysis. Stoichiometric copper reagents can also be used, and among these, organocuprates are the most common (they are more reactive than the corresponding neutral organocopper(I) compounds). The cuprate counterion may affect the addition and subsequent enolate reaction in subtle ways. When unsymmetrical cuprates are employed, the group whose carbon-copper bond contains less s character is almost always transferred to the β-position. A variety of other stabilized anions can also be used in the β-addition step.

Numerous unsaturated carbonyl substrates have also been employed in the reaction. Because the addition step is highly sensitive to sterics, β-substituents are likely to slow the reaction. Acetylenic and allenic substrates react to give products with some retained saturation.

Considerations of the electrophile should take into account the nature of the conjugate enolate generated after the first step. Relatively reactive alkylating agents should be used, especially in cases involving the addition of cuprates (enolates resulting from the addition of cuprates are often sluggish). Oxophilic electrophiles should be avoided, if C-alkylation is desired. Electrophiles should also lack hydrogens acidic enough to be deprotonated by an enolate.

Synthetic Applications
A large number of examples of vicinal difunctionalization of unsaturated carbonyls exist in the literature. In one example, Schlessinger employed the difunctionalization of unsaturated lactone 1 en route to isostegane. This transformation was accomplished in one pot. Because the reaction creates two new bonds with a moderately high degree of stereocontrol, it represents a highly convergent synthetic methodology.

Typical Conditions
Organometallic nucleophiles used for conjugate additions are most often prepared in situ. The use of anhydrous equipment and inert atmosphere is necessary. Because these factors are sometimes difficult to control and the strength of freshly prepared reagents can vary substantially, titration methods are necessary to verify the purity of reagents. A number of efficent titration methodologies exist.

Usually, vicinal difunctionalizations are carried out in one pot, without the intermediacy of a neutral protected enolate. However, in specific cases it may be necessary to protect the intermediate of β-addition. Before reaching this point, however, solvent and nucleophile screens, order of addition adjustments, and counterion adjustments can be made to optimize the one-pot process for a particular combination of carbonyl compound, nucleophile, and alkylating (or acylating) agent. Solvent adjustments between the two steps are common; if one solvent is used, tetrahydrofuran is the solvent of choice. Polar aprotic solvents should be avoided for the conjugate addition step. Concerning temperature, conjugate additions are usually carried out at low temperatures (-78 °C), while alkylations are carried out at slightly higher temperatures (0 to -30 °C). Less reactive alkylating agents may require room temperature.

Example Procedure
To 6.25 g (50 mmol) of 4,4-dimethyl-2-cyclohexen-1-one and 0.5 g (5.6 mmol) of cuprous cyanide in 400 mL of diethyl ether at –23° under argon was added 100 mL (~0.75 M in diethyl ether) of 5-trimethylsilyl-4-pentynylmagnesium iodide during 4 hours. Methyl chloroformate (8 mL, 100 mmol) was added and stirring continued for 1 hour at –23° and 0.5 hour at room temperature. Hydrochloric acid (100 mL, 2.0 M) then was added and the organic phase separated and dried with magnesium sulfate. The solvent was removed and the residue chromatographed on silica gel using 5% diethyl ether–petroleum ether to give methyl 3,3-dimethyl-6-oxo-2-[5-(trimethylsilyl)-4-pentynyl]cyclohexanecarboxylate, 9.66 g (60%). IR 2000, 2140, 1755, 1715, 1660, 1615, 1440, 1280, 1250, 1225, 1205, and 845 cm–1; 1H NMR ( CDCl3) δ 0.13 (s, 9H), 0.93 (s, 3H), 1.02 (s, 3H), 1.2–2.3 (m, 11H), 3.74 (s, 3H). Anal. Calc. for C18H30O3Si: C, 67.05; H, 9.4. Found: C, 67.1; H, 9.65.